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PROCESS FOR THE PREPARATION OF ELIGLUSTAT INTERMEDIATE

IP.com Disclosure Number: IPCOM000246181D
Publication Date: 2016-May-13
Document File: 7 page(s) / 134K

Publishing Venue

The IP.com Prior Art Database

Related People

Kangying Li: AUTHOR [+2]

Abstract

The present disclosure provides a process for the preparation of Eliglustat intermediate (1R,2R)-2-amino-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(pyrrolidin-1-yl)propan-1-ol.

This text was extracted from a PDF file.
This is the abbreviated version, containing approximately 21% of the total text.

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PROCESS FOR THE PREPARATION OF ELIGLUSTAT INTERMEDIATE

     Eliglustat is the non-proprietary name for N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- hydroxy-3-(pyrrolidin-1-yl)propan-2-yl) octanamide, which is provided as a tartrate salt in commercially available CerdelgaTM. Eliglustat tartrate was approved by the FDA in August 2014 for the treatment of Gaucher disease.

     The present document discloses a process for the preparation of Eliglustat intermediate 1, which is shown in Scheme 1.

Scheme 1. Disclosed process for the preparation of Eliglustat intermediate 1.

O O

OH

    NHBoc 5

OH NHBoc

OH

step 1

O O

O O

OTs

step 2

O NBoc OTs

4

3

OH NH2

O O

O O

step 3

O NBoc
N

step 4

N

2

1

      In a first aspect, provided herein is a process for the preparation of a compound of Formula 4, the process comprising reaction of a compound of Formula 5, in the presence of a first base and a first organic solvent, with p-toluenesulfonyl chloride to afford a compound of Formula 4.

     An amount of p-toluenesulfonyl chloride with respect to the compound of Formula 5, expressed in mole equivalents, of about 1 to about 2 equivalents, preferably 1.1 to 1.2 equivalents may be used.

     A first base is not particularly limited and may be a tertiary amine base such as triethylamine or diisopropyl ethyl amine or a heterocyclic base such as pyridine.

     An amount of said first base with respect to the compound of Formula 5, expressed in mole equivalents, of about 1.1 to about 1.8 equivalents, preferably 1.2 equivalents may be used.

     A first organic solvent is not particularly limited provided that it is compatible with the reaction. A solvent may be selected from the group consisting of ethers, such as methyl t-butyl ether and tetrahydrofuran, esters, such as isopropyl acetate and ethyl acetate, ketones, such as acetone and


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methyl isobutyl ketone, aromatic hydrocarbons, such as toluene and chlorinated hydrocarbons such as dichloromethane. A preferred solvent is tetrahydrofuran.

     The reaction of a compound of Formula 5 and p-toluenesulfonyl chloride may be conducted in the presence of 4-(N,N-dimethylamino)pyridine (DMAP). A suitable amount of DMAP, expressed in weight (wt) % with respect to the compound of Formula 5, may be in the range of about 2 % to about 10 %, preferably 2 %.

     The reaction of a compound of Formula 5 and p-toluenesulfonyl chloride may be conducted within a temperature range of about -20 °C to about 30 °C, preferably between about 0 °C to about 10 °C.

     In a preferred process, upon reaction completion, water is added to dissolve by-product acid salt of the first base. Depending on the reaction solvent, the product can be isolated from the water/organic solvent mixture by filtration or by phase separation. Alternatively, the by-product acid salt of the first base can be carried through to the next step without any significant impact on the subsequent reaction. The crude product of this step may be further purified by providing and maintaining a sus...